1. Field of the Invention
This invention is in the field of anti-atherosclerotic agents and specifically relates to compounds, compositions and methods for treating atherosclerotic conditions such as dysliproteinimias and coronary heart disease. This invention specifically relates to substituted tetrahydro-1,3,5-triazin-2[1H]-thione derivatives that elevate HDL cholesterol concentration and which may be useful for the treatment of atherosclerotic conditions and coronary heart disease.
Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL-C) concentrations (Russ et al, Am. J. Med., 11 (1951) 480-483; Gofman et al. Circulation, 34 (1966), 679-697; Miller and Miller, Lancet, 1 (1975), 16-19; Gordon et al., Circulation, 79 (1989), 8-15; Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381; Badimon et al., Lab. Invest., 60 (1989), 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller al., Br. Med. J., 282 (1981), 1741-1744).
There are several mechanisms by which HDL may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis, 6 (1986), 434-441). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res., 9 (1968), 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., Circulation, 66 (Suppl. I) (1982), 102; McKinnon et al., J. Biol. Chem., 261 (1986), 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem., 253, (1978), 1834-1841; Lagocki and Scanu, J. Biol. Chem., 255 (1980), 3701-3706; Schaefer et al., J. Lipid Res., 23 (1982), 1259-1273). Accordingly, agents which increase HDL cholesterol concentrations would be of utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
2. Prior Art
U.S. Pat. No. 3,505,057 and U.S. Pat. No. 3,505,323 (E.I. DuPont de Nemours and Co, Apr. 7, 1970) disclose 1-aryl-tetrahydro-s-triazin-2[1H]-thiones and their use as herbicidal agents.
U.S. Pat. No 4,193,994 (Pfizer Inc., Mar. 18, 1980) discloses 1-(o-tolyl)-3,5-disubstituted tetrahydro-s-triazin-2[1H]-thiones and their use as acaricidal agents.
Zhurnal Obshchei Khimii, Vol. 61, No. 8, (1991), pp. 1870-1873, English translation (1992), pp. 1728-1730 (Plenum Publishing Co.), report the synthesis of 1-aryl-3,5-di-(tert-butyl)-terahydro-triazin-2[1H]-thiones with no stated specific utility.
Khim, Geterotsikl, Soedin. (1986), pp. 976-980, reports the mass spectra of 1-aryl-3,5-disubstituted-tetrahydro-triazin-2[1H]-thiones with no stated specific utility.